Patent NZ-337336-A (NZ)
Title: N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
Inventor: VENKATESAN ARANAPAKAM MUDUMBAI
IPC: A61K31/165
Filed: 1998-02-17
Abstract: The compounds of formula I are inhibitors of matrix metalloproteinases (MMPs) and TNF-a converting enzyme (TACE), and may be used in the treatment of arthritis, tumour metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection. In formula (I): R1 is C1-18 alkyl, C3-18 alkenyl, C3-18 alkynyl, C6-10 aryl, C3-8 cycloalkyl, saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing a heteroatom selected from O, S or NR7, or heteroaryl-(CH2)0-6 wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N; all of which may be substituted with groups selected independently from R5; A is -S-, -SO- or S02-; R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or NR7 optionally having one or two double bonds; R4 is hydrogen, C1-6 alkyl, C3-18 alkenyl, C3-18 alkynyl, phenyl or naphthyl, C3-8 cycloalkyl or bicycloalkyl, saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing a heteroatom selected from O, S or NR7; all of which may be substituted with groups selected independently from R5; R5 is H, C7-11 aroyl, C2-6 alkanoyl, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, F, Cl, Br, I, CN, CHO, C1-6 alkoxy, aryloxy, heteroaryloxy, C3-6 alkenyloxy, C3-6 alkynyloxy, C1-6 alkoxyaryl, C1-6 alkoxyheteroaryl, C1-6 alkylamino-C1-6 alkoxy, C1-2 alkylene dioxy, aryloxy-C1-6 alkyl amine, C1-12 perfluoro alkyl, S(O)n-C1-6 alkyl, S(O)n-aryl (where n is 0, 1 or 2), OCOO C1-6 alkyl, OCOO aryl, OCONR6, COOH, COO C1-6 alkyl, COO aryl, CONR6R6, CONHOH, NR6R6, S02NR6R6, NR6SO2aryl, -NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2-C1-6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3-8 cycloalkyl or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing a heteroatom selected from O, S or NR7;  R6 is H, C1-8 alkyl optionally substituted with OH, C3-6 alkenyl, C3-6 alkynyl, C1-6 perfluoro alkyl, S(O)n-C1-6 alkyl S(O)n aryl (where n is 0, 1 or 2), or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7; and R7 is C7-11 aroyl, C2-6 alkanoyl, C1-12 perfluoro alkyl, S(O)n-C1-6 alkyl, S(O)n- aryl (where n is 0, 1 or 2), COO-C1-6-alkyl, COOaryl, CONHR6, CONR6R6, CONHOH, SO2NR6R6, SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO-C1-6-alkyl, CONHSO2aryl, aryl or heteroaryl, or optionally substituted C1-18 alkyl, C3-18 alkenyl, C3-18 alkynyl, C7-16 arylalkyl, C13-18 biphenylalkyl, C8-16 arylalkenyl, C4-12 cycloalkylalkyl or bicycloalkylalkyl or a saturated or unsaturated mono or bicyclic heterocycle containing a heteroatom selected from O, S or N-C1-6 alkyl, (wherein the substituting groups are selected from R5),or R8R9N-C1-6-alkoxyaryl-C1-6-alkyl, (wherein R8 and R9 are independently selected from C1-6 alkyl, or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom).